1. Field of the Invention
The present invention relates to a micronized alkoxyimidazol-1-ylmethyl biphenyl carboxylic acid crystalline compound having improved stability. This invention also relates to pharmaceutical compositions comprising the stable micronized compound, processes for preparing the stable micronized compound, and methods of using the stable micronized compound to treat diseases such as hypertension.
2. State of the Art
U.S. Publication Nos. 2008/0269305 and 2009/0023228, both to Allegretti et al. filed on Apr. 23, 2008, disclose novel compounds that possess AT1 receptor antagonist activity and neprilysin (NEP) enzyme inhibition activity, the disclosures of which are incorporated herein by reference. In particular, the compound, 4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid is described in these applications. The chemical structure of this compound is represented by formula I:

When preparing compounds for long term storage and when preparing pharmaceutical compositions and formulations, it is often desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent. It is also advantageous to have a crystalline form that has a relatively high melting point, which allows the material to be processed without significant decomposition. A crystalline freebase form of the compound of formula I is described in U.S. Publication No. 2010/0081697, to Chao et al. filed on Sep. 29, 2009, the disclosure of which is incorporated herein by reference.
Although this crystalline material has been found to be stable, it is desirable to further enhance the stability, in particular during mechanical processing such as milling or micronization, since particle size reduction of this crystalline material may have an adverse effect on its chemical stability. Attempts have been made to address chemical stability brought about by mechanical stress, in for example, U.S. Publication No. 2007/0082055 to Kurgan et al., where candesartan cilexetil was found to have improved stability when fine particles were slurried in an alcohol solvent. However, such techniques are often specific to particular crystalline forms.
Accordingly, there remains a need to obtain a stable micronized form of 4′-{2-ethoxy-4-ethyl-5-[((S)-2-mercapto-4-methylpentanoylamino)methyl]imidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid.